NM_004568.6:c.881C>G

Variant names:

• chr6-2948548-G-C
• NM_004568.6:c.881C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004568.6(SERPINB6):​c.881C>G​(p.Ala294Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINB6 NM_004568.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

Genes affected

SERPINB6 (HGNC:8950): (serpin family B member 6) The protein encoded by this gene is a member of the serpin (serine proteinase inhibitor) superfamily, and ovalbumin(ov)-serpin subfamily. It was originally discovered as a placental thrombin inhibitor. The mouse homolog was found to be expressed in the hair cells of the inner ear. Mutations in this gene are associated with nonsyndromic progressive hearing loss, suggesting that this serpin plays an important role in the inner ear in the protection against leakage of lysosomal content during stress, and that loss of this protection results in cell death and sensorineural hearing loss. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB6	NM_004568.6	c.881C>G	p.Ala294Gly	missense_variant	Exon 7 of 7	ENST00000380539.7	NP_004559.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB6	ENST00000380539.7	c.881C>G	p.Ala294Gly	missense_variant	Exon 7 of 7	3	NM_004568.6	ENSP00000369912.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D;D;D;D;D;D;T;T;.;D;D;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.76	.;.;.;.;.;.;.;T;.;T;.;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.6	H;H;H;H;H;H;H;.;.;.;H;H;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.5	D;D;D;D;.;D;.;.;.;.;.;D;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.027	D;D;D;D;.;D;.;.;.;.;.;D;.
Sift4G	Uncertain	0.041	D;D;D;D;.;D;.;D;.;.;.;D;.
Polyphen		0.35	B;B;B;B;B;B;B;.;.;.;B;B;.
Vest4		0.52
MutPred		0.73		Gain of disorder (P = 0.0595);Gain of disorder (P = 0.0595);Gain of disorder (P = 0.0595);Gain of disorder (P = 0.0595);Gain of disorder (P = 0.0595);Gain of disorder (P = 0.0595);Gain of disorder (P = 0.0595);.;.;.;Gain of disorder (P = 0.0595);Gain of disorder (P = 0.0595);.;
MVP		0.94
MPC		0.33
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.86
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-2948782;